EP2148883A1 - Verfahren zur herstellung von reinem prulifloxacin - Google Patents

Verfahren zur herstellung von reinem prulifloxacin

Info

Publication number
EP2148883A1
EP2148883A1 EP08719708A EP08719708A EP2148883A1 EP 2148883 A1 EP2148883 A1 EP 2148883A1 EP 08719708 A EP08719708 A EP 08719708A EP 08719708 A EP08719708 A EP 08719708A EP 2148883 A1 EP2148883 A1 EP 2148883A1
Authority
EP
European Patent Office
Prior art keywords
prulifloxacin
water
process according
organic solvent
immiscible organic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08719708A
Other languages
English (en)
French (fr)
Inventor
Tarun Kant Sharma
Raghuram Morampudi
Shanmugam Srinivasan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of EP2148883A1 publication Critical patent/EP2148883A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for the preparation of prulifloxacin.
  • the present invention further relates to prulifloxacin having purity of about 99% or above.
  • Prulifloxacin is chemically 6-fluoro-l-methyl-7- ⁇ 4-[(5-methyl-2-oxo-l,3-dioxol-4- yl)methyl]piperazin-l-yl ⁇ -4-oxo-4H-[l,3]thiazeto[3,2- ⁇ ]quinoline-3-carboxylic acid of Formula I having the structure as depicted below:
  • Prulifloxacin has significant antibacterial activity and has been marketed as a synthetic antibacterial agent.
  • U.S. Patent No. 5,086,049 provides a process for the preparation of prulifloxacin by reacting 6-fluoro-l-methyl-4-oxo-7-piperazin-l-yl-4H- [l,3]thiazeto[3,2- ⁇ ]quinoline-3-carboxylic acid of Formula II,
  • FORMULA II and 4-(bromomethyl)-5-methyl-l,3-dioxol-2-one of Formula III FORMULA III using N,N-dimethylformamide as a solvent.
  • 4-(Bromomethyl)-5-methyl-l,3-dioxol-2-one of Formula III is used in excess to one mole of the compound of Formula II.
  • the process provided in U.S. Patent No. 5,086,049 further involves concentrating the reaction mixture, pouring the residue into water and isolating prulifloxacin by filtration. The resulting prulifloxacin is recrystallized from chloroform-methanol.
  • U.S. Patent No. 5,086,049 does not provide any method to remove the unreacted or the excess of 4-(bromomethyl)-5-methyl-l,3-dioxol-2-one of Formula III used as a starting material.
  • the present inventors have observed that it is difficult to obtain prulifloxacin with pharmaceutically acceptable purity by following the process provided in U.S. Patent No. 5,086,049, which is typically contaminated by process related impurities including 4-(bromomethyl)-5-methyl-l,3-dioxol-2-one.
  • the present inventors have developed a process for the preparation of prulifloxacin which significantly reduces process-related impurities.
  • the present process includes the extraction of prulifloxacin in the aqueous layer in the form of its acid addition salt, and thereby facilitates the removal of organic soluble impurities including unreacted or excess 4-(bromomethyl)-5-methyl-l,3-dioxol-2-one of Formula III.
  • the impurities including 4-(bromomethyl)-5-methyl- l,3-dioxol-2-one can be reduced to an amount of less than about 1% and prulifloxacin can be obtained with a purity of about 99% or above.
  • a process for the preparation of prulifloxacin comprising: a) reacting a compound of Formula II with a compound of Formula III to obtain prulifloxacin;
  • step b) contacting the prulifloxacin obtained in step a) with an acid in a biphasic solvent system, wherein the biphasic solvent system comprises water and a water- immiscible organic solvent; c) separating the aqueous layer from the reaction mixture obtained in step b); d) treating the aqueous layer with a base; and e) isolating prulifloxacin.
  • a biphasic solvent system comprises water and a water- immiscible organic solvent
  • steps b - e above may be carried out with prulifloxacin made from any process however.
  • the compounds of Formula II and Formula III may be prepared according to the methods provided in U.S. Patent No. 5,086,049.
  • the compounds of Formula II and Formula III are reacted in the presence of an organic solvent and a base.
  • the amount of compound of Formula III is equimolar or excess to one mole of the compound of Formula II.
  • the compound of Formula III may be used in excess to one mole of the compound of Formula II.
  • the organic solvent may be selected from, for example, N,N-dimethyl formamide, dimethylsulfoxide and diglyme.
  • the base may be, for example, an alkali metal carbonate.
  • the reaction can be effected by stirring the reaction mixture at from about O to about 50 C. After the completion of the reaction, prulifloxacin is separated from the reaction mixture.
  • the separation may be carried out by pouring the reaction mixture into water and filtering prulifloxacin as a solid.
  • the prulifloxacin so obtained is dissolved in a water-immiscible organic solvent.
  • the water-immiscible organic solvent can be selected from, for example, chloroform, cyclohexane, dichloromethane, 1,2- dichloroethane, diethyl ether, hexane, pentane, methyl-t-butyl ether, ethyl acetate, carbon tetrachloride or the like.
  • the water-immiscible organic solvent can also be a mixture of the foregoing with a Ci_ 3 alkanol.
  • the water-immiscible organic solvent containing prulifloxacin is treated with water.
  • the biphasic reaction mixture so obtained is treated with an inorganic or an organic acid.
  • the water immiscible organic solvent containing prulifloxacin is treated with an aqueous solution of an inorganic or an organic acid.
  • Hydrochloric acid and hydrobromic acid can be used as the acid, for example.
  • the aqueous layer is subsequently separated from the reaction mixture and treated with an inorganic or an organic base to precipitate prulifloxacin as a free base.
  • An inorganic base selected from a group consisting of alkali metal carbonates or hydroxides, and alkaline earth metal carbonates or hydroxides can be used.
  • the precipitated solid prulifloxacin can be isolated from the aqueous layer by further layer separation.
  • the aqueous layer containing precipitated prulifloxacin is treated with a water- immiscible organic solvent.
  • the water-immiscible organic solvent can be selected from, for example, chloroform, cyclohexane, dichloromethane, 1 ,2- dichloroethane, diethyl ether, hexane, pentane, methyl-t-butyl ether, ethyl acetate, carbon tetrachloride or the like.
  • the water-immiscible organic solvent can also be a mixture with a Ci_ 3 alkanol.
  • the organic layer is separated from the reaction mixture and the solvent is removed by concentration to obtain prulifloxacin as a solid.
  • the precipitated solid prulifloxacin can be directly isolated from the aqueous layer by filtration.
  • the prulifloxacin so obtained is further recrystallized to obtain prulifloxacin having purity of about 99% or above.
  • the recrystallization can be carried out from a mixture of a water-immiscible organic solvent and a Ci -3 alkanol, for example, a mixture of chloroform and ethanol.
  • prulifloxacin having purity of about 99% or above is provided.
  • a pharmaceutical composition comprising prulifloxacin having purity of about 99% or above, and optionally containing one or more excipients and/or diluents is provided.
  • a method of treating bacterial infections in humans and animals which comprises administering to human or animal in need thereof an antibacterially effective amount of prulifloxacin having purity of about 99% or above is provided.
  • reaction mixture was poured into water (1250 ml).
  • the solid obtained was filtered, washed with water (100 ml), and subsequently dissolved in a mixture of chloroform: methanol (7:3; 1250 ml).
  • the lower organic layer was separated and water (500 ml) was added to the organic layer.
  • a dilute aqueous solution of hydrochloric acid was added to the biphasic reaction mixture to adjust p ⁇ to 0.8 to 1.0.
  • the reaction mixture was stirred for 15 minutes, allowed to settle and the upper aqueous layer was separated. The process was repeated twice and the aqueous layers were combined.
  • Activated charcoal (10%) was added to the combined aqueous layer and stirred for 30 minutes, filtered and cooled to 20° to 25° C.
  • the p ⁇ of the reaction mixture was adjusted to 6.5 to 7.0 by adding an aqueous solution of sodium bicarbonate.
  • the solid obtained was extracted with chloroform (375 ml), stirred for 15 minutes and the organic layer was separated.
  • the aqueous layer was further extracted with a mixture of chloroform: methanol (7:3 ratio; 50 ml).
  • the combined organic layer was distilled under vacuum at 35° to 40° C to recover the solvent up to 125 ml.
  • the reaction mass so obtained was stirred for 3 to 4 hours at 28° to 30° C, filtered and washed with chilled chloroform (50 ml).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP08719708A 2007-03-14 2008-03-14 Verfahren zur herstellung von reinem prulifloxacin Withdrawn EP2148883A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN545DE2007 2007-03-14
PCT/IB2008/050972 WO2008111016A1 (en) 2007-03-14 2008-03-14 Process for the preparation of pure prulifloxacin

Publications (1)

Publication Number Publication Date
EP2148883A1 true EP2148883A1 (de) 2010-02-03

Family

ID=39562800

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08719708A Withdrawn EP2148883A1 (de) 2007-03-14 2008-03-14 Verfahren zur herstellung von reinem prulifloxacin

Country Status (3)

Country Link
US (1) US20110034690A1 (de)
EP (1) EP2148883A1 (de)
WO (1) WO2008111016A1 (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009093268A1 (en) * 2008-01-23 2009-07-30 Ind-Swift Laboratories Limited Process for the preparation of highly pure prulifloxacin
WO2011031745A1 (en) 2009-09-09 2011-03-17 Achaogen, Inc. Antibacterial fluoroquinolone analogs
CN102093393B (zh) * 2009-12-15 2014-03-26 南京长澳医药科技有限公司 一种制备普卢利沙星及其中间产物的方法
CN102198135B (zh) * 2010-03-22 2013-05-08 北京联木医药技术发展有限公司 一种新型稳定的普卢利沙星盐酸盐在制备抗感染药物中的应用
IN2012MN02925A (de) 2010-06-30 2015-05-22 Cipla Ltd
CN103113392B (zh) * 2013-02-20 2016-01-20 济川药业集团有限公司 一种普卢利沙星的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0751579B2 (ja) * 1987-11-07 1995-06-05 日本新薬株式会社 キノリンカルボン酸誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008111016A1 *

Also Published As

Publication number Publication date
WO2008111016A1 (en) 2008-09-18
US20110034690A1 (en) 2011-02-10

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